Introduction
Glycoproteins and glycolipids play important roles in biological phenomenon1. Critical to this biological activity is the sialic acid (SA) family of sugars or carbohydrates, which is principally found as the terminal carbohydrate residue in glycoconjugates. A link between the presence of these cell-surface SAs and the metastatic potential of cancer cells is now well established2. In fact metastatic potential is positively correlated with an increased level of cell-surface sialylation. Intervention therefore in the biosynthesis of SA and in particular the glycoconjugate structures that contain SA could lead to significant alteration in the properties of tumour cells.
The main objective of this research work has been the design and synthesis of SA derivatives – followed by assaying of the derivatives to identify modified SAs as substrates and/or inhibitors for a key enzyme (CMP-SA synthetase) in the biosynthetic pathway of SA containing glycoconjugate structures.
Results
Based on modeling studies of the murine CMP-SA synthetase, strategic sites on SA have been identified and modifications made. Results will be presented in a generalized manner of C-9 oxidised modifications made on the glycerol side chain to explore the positively charged glycerol pocket of CMP-SA-synthetase3. Additionally, the recently developed Saturation-Transfer-Difference (STD) NMR assay technique used to in-part determine the interaction specificity of the SA derivatives with the CMP-SA synthetase enzyme will be presented.
Conclusions
STD NMR assay data on SA-derivatives will help to guide our ongoing work towards the development of SA-based inhibitors of cell-surface sialylation – and potentially cellular metastasis.
References
1. Haselhorst et al. Nat. Chem. Biol.2009, 91-93.
2. i) Chen, Varki ACS Chem. Biol. 2010, 5, 163-176. ii) Schauer Curr. Opin. Struct. Biol. 2009, 19, 507-514.
3. Kiefel et al. Tett. Lett. 2011, 52, 98-100.